A natural compound produced by gut bacteria after consuming certain foods has been shown to reverse anxiety-like behaviors in rats by repairing the tiny power-generating structures within brain cells. The study provides a significant new piece of evidence directly linking anxiety to mitochondrial dysfunction and suggests a novel therapeutic avenue that moves beyond merely managing symptoms to correcting an underlying biological cause.
The research, led by scientists at the Swiss Federal Institute of Technology Lausanne (EPFL), found that administering Urolithin A to anxious rats not only restored normal behavior but also fixed structural and functional damage in the neurons of a key brain region associated with emotion. Because Urolithin A has a strong safety record in humans, the findings pave the way for potential clinical trials to investigate a new generation of treatments for anxiety disorders, which affect an estimated 14% of the global population annually. The work highlights a systemic, diet-based approach in contrast to more invasive genetic methods previously used to study the brain’s energy machinery.
The Cellular Engine of Anxiety
For years, researchers have noted a correlation between mood disorders and problems within mitochondria, the organelles inside every cell responsible for producing energy. In the brain, an exceptionally high-energy organ, healthy mitochondria are critical for fueling the processes that allow neurons to communicate, adapt, and survive. When mitochondria become dysfunctional, they produce less energy and release damaging molecules, a state that has been observed in both animal models and human patients with anxiety.
This study focused specifically on the nucleus accumbens, a brain region central to processing motivation, pleasure, and emotional responses. Previous work by the EPFL team, led by Professor Carmen Sandi at the Laboratory of Behavioral Genetics, had already pointed to this area as being vulnerable to mitochondrial problems in states of high anxiety. The new research sought to determine if actively repairing these cellular power plants could do more than just stop further damage—it aimed to see if it could reverse the behavioral symptoms of anxiety itself.
A Promising Postbiotic Compound
What is Urolithin A?
Urolithin A is not a compound found directly in food but is a metabolite produced by our gut microbiome. When we consume foods rich in polyphenols known as ellagitannins—found in pomegranates, walnuts, and some berries—specific bacteria in the gut convert them into urolithins. Urolithin A is already known to be a powerful agent for promoting mitochondrial health. It works by stimulating a cellular quality-control process called mitophagy.
The Role of Mitophagy
Mitophagy is the essential process by which a cell identifies and removes old, damaged, or dysfunctional mitochondria. This cellular housekeeping makes way for the generation of new, healthy ones, ensuring the cell has a reliable energy supply. In conditions of chronic stress and anxiety, this recycling system can become imbalanced. The EPFL researchers found that the molecular machinery governing mitophagy was consistently disrupted in the anxious rats, a deficit that Urolithin A treatment was able to correct.
Study Design and Key Findings
The researchers took a systematic and non-invasive approach to test the compound’s effects. Instead of using complex genetic tools to alter mitochondria directly in the brain, they incorporated Urolithin A into the diet of two different rat models of anxiety. This method more closely resembles how such a compound might be used as a nutritional supplement in humans. The team then performed a combination of behavioral tests and in-depth cellular analysis.
Behavioral Turnaround
The results of the intervention were described as striking. Anxious rats that consumed the Urolithin A-enriched diet exhibited a complete reversal of their high-anxiety behaviors, what the study called a “robust anxiolytic effect.” They spent more time exploring open spaces and showed fewer signs of fear and hesitation compared to anxious rats on a standard diet. Crucially, the compound had no noticeable behavioral effect on rats that were already low-anxious. This suggests that Urolithin A does not act as a general sedative but instead works specifically to correct circuits that have been disturbed by mitochondrial dysfunction.
Evidence of Cellular Repair
When the scientists examined the brain tissue of the treated rats, they found clear evidence of biological recovery. The structure and function of neurons in the nucleus accumbens were restored. This included the repair of dendritic spines, the tiny protrusions on neurons that receive signals from other brain cells and are vital for proper circuit function. Furthermore, levels of a key protein called Mitofusin 2, which is critical for maintaining mitochondrial health and has been previously linked to anxiety behaviors, returned to normal levels in the treated animals.
A New Path for Therapeutics
Current medications for anxiety, while helpful for many, primarily target neurotransmitter systems to manage symptoms. They do not address the underlying cellular energetics that may contribute to the disorder’s origin. These drugs can also come with significant side effects, including dependency or emotional blunting. By successfully targeting and repairing a core biological deficit, Urolithin A supplementation represents a fundamentally different strategy. It opens the door to nutritional interventions designed to be more precise and potentially have fewer side effects.
From Animal Models to Human Health
A major advantage of studying Urolithin A is its established safety profile in human clinical trials for other applications, primarily related to muscle health. This existing data could significantly accelerate its translation from laboratory research into human studies for neuropsychiatric conditions. Professor Sandi confirmed that moving toward clinical trials is the team’s next major goal.
While the results are promising, it is important to note that these findings are from rodent studies and are not yet directly applicable to humans. Future research will need to confirm if the same mechanisms are at play in human anxiety disorders and determine appropriate dosages and treatment durations. Nonetheless, this work provides a powerful validation of the mitochondrial hypothesis of anxiety and offers a tangible path forward for developing a new class of therapeutics rooted in the fundamental energy processes of the brain.